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Peer-reviewedCC BY 4.0Organogenesis

Functional characterization of a non-coding RUNX1T1 variant in a kindred with esophageal atresia

  • Nadav Agam1,2
  • Sarit Aharoni1,2
  • Baruch Yerushalmi2,3
  • Galina Ling2,3
  • Elad Brav1,2
  • Katya Oustinov1,2
  • Vadim Dolgin1,2,4
  • Ofek Freund1,2
  • Amit Safran1,2
  • Matan M. Jean1,2
  • Tomer Poleg1,2
  • Nitza Newman2,5
6 more authors
  • Zaki Assi2,5
  • Assaf Ben Zvi6
  • Ramon Y. Birnbaum6
  • Suad Sheikh-Suliman6
  • Uri Abdu6
  • Ohad S. Birk1,2,4,7
7 affiliations
  1. 1Morris Kahn Laboratory of Human Genetics, National Institute of Biotechnology in the Negev, Ben Gurion University, Be'er Sheva, Israel
  2. 2Faculty of Health Sciences, Ben Gurion University, Be'er Sheva, Israel
  3. 3Pediatric Gastroenterology Unit, Saban Children's Hospital, Soroka Medical Center, Be'er Sheva, Israel
  4. 4Genetics Institute, Soroka Medical Center, Be'er Sheva, Israel
  5. 5Department of Pediatric Surgery, Soroka Medical Center, Be'er Sheva, Israel
  6. 6Department of Life Sciences, Ben-Gurion University, Be'er Sheva, Israel
  7. 7Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat-Gan, Israel
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Abstract

Introduction: Esophageal atresia (EA) is a congenital foregut malformation with substantial genetic heterogeneity. While coding variants explain some syndromic cases, the molecular basis of non-syndromic EA remains largely unknown. We investigated an Israeli-Bedouin kindred with a high incidence of non-syndromic EA.

Methods: Three of ten affected individuals underwent whole-exome/genome sequencing. Following variant filtering and prioritization using population databases and in silico tools, the candidate non-coding variant underwent Sanger sequencing in all five available affected individuals. Functional effects were assessed by minigene splicing assays, quantitative PCR, dual-luciferase reporter assays, and a fly overexpression model.

Results: Sequencing data variant analysis of 3 affected individuals identified a shared heterozygous deep-intronic RUNX1T1 variant (chr8:91994544G > A, hg38), subsequently verified in the five participating affected individuals. Although incorporated into a rare RUNX1T1 transcript, the variant did not affect splicing. Instead, it increased expression of canonical RUNX1T1 isoforms and enhanced reporter activity, consistent with a regulatory gain-of-function effect. RUNX1T1 ortholog (nvy) global overexpression in Drosophila resulted in morphological alterations of the feeding apparatus, including reduced rigidity and elongation of the labral sense organ.

Conclusion: In a kindred with apparently partially penetrant dominant non-syndromic EA, we identified a novel non-coding RUNX1T1 variant with functional evidence of a regulatory gain-of-function effect. These findings implicate RUNX1T1 dysregulation as a contributor to EA pathogenesis and highlight the importance of non-coding regulatory variation in congenital foregut malformations.

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Cite

BibTeXRIS
BibTeX
@article{agam2026functional,
  title = {{Functional characterization of a non-coding RUNX1T1 variant in a kindred with esophageal atresia}},
  author = {Nadav Agam and Sarit Aharoni and Baruch Yerushalmi and Galina Ling and Elad Brav and Katya Oustinov and Vadim Dolgin and Ofek Freund and Amit Safran and Matan M. Jean and Tomer Poleg and Nitza Newman and Zaki Assi and Assaf Ben Zvi and Ramon Y. Birnbaum and Suad Sheikh-Suliman and Uri Abdu and Ohad S. Birk},
  journal = {Organogenesis},
  year = {2026},
  month = oct,
  doi = {10.1080/15476278.2026.2754587},
  url = {https://doi.org/10.1080/15476278.2026.2754587},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Functional characterization of a non-coding RUNX1T1 variant in a kindred with esophageal atresia
AU  - Nadav Agam
AU  - Sarit Aharoni
AU  - Baruch Yerushalmi
AU  - Galina Ling
AU  - Elad Brav
AU  - Katya Oustinov
AU  - Vadim Dolgin
AU  - Ofek Freund
AU  - Amit Safran
AU  - Matan M. Jean
AU  - Tomer Poleg
AU  - Nitza Newman
AU  - Zaki Assi
AU  - Assaf Ben Zvi
AU  - Ramon Y. Birnbaum
AU  - Suad Sheikh-Suliman
AU  - Uri Abdu
AU  - Ohad S. Birk
PY  - 2026
DA  - 2026/10/30
JO  - Organogenesis
DO  - 10.1080/15476278.2026.2754587
UR  - https://doi.org/10.1080/15476278.2026.2754587
AB  - Introduction: Esophageal atresia (EA) is a congenital foregut malformation with substantial genetic heterogeneity. While coding variants explain some syndromic cases, the molecular basis of non-syndromic EA remains largely unknown. We investigated an Israeli-Bedouin kindred with a high incidence of non-syndromic EA.  Methods: Three of ten affected individuals underwent whole-exome/genome sequencing. Following variant filtering and prioritization using population databases and in silico tools, the candidate non-coding variant underwent Sanger sequencing in all five available affected individuals. Functional effects were assessed by minigene splicing assays, quantitative PCR, dual-luciferase reporter assays, and a fly overexpression model.  Results: Sequencing data variant analysis of 3 affected individuals identified a shared heterozygous deep-intronic RUNX1T1 variant (chr8:91994544G > A, hg38), subsequently verified in the five participating affected individuals. Although incorporated into a rare RUNX1T1 transcript, the variant did not affect splicing. Instead, it increased expression of canonical RUNX1T1 isoforms and enhanced reporter activity, consistent with a regulatory gain-of-function effect. RUNX1T1 ortholog (nvy) global overexpression in Drosophila resulted in morphological alterations of the feeding apparatus, including reduced rigidity and elongation of the labral sense organ.  Conclusion: In a kindred with apparently partially penetrant dominant non-syndromic EA, we identified a novel non-coding RUNX1T1 variant with functional evidence of a regulatory gain-of-function effect. These findings implicate RUNX1T1 dysregulation as a contributor to EA pathogenesis and highlight the importance of non-coding regulatory variation in congenital foregut malformations.
SN  - 1547-6278
SN  - 1555-8592
ER  -